Approximately 5-15% of the population of the United States over age 65 (1.24 million) has Alzheimer's disease. This disease is the most frequent cause of institutionalization for long-term care. In 1983, more than $27 billion was spent in the U.S. in health care for Alzheimer's afflicted individuals.
Six basic research areas of Alzheimer's have been defined by R. J. Wurtman, Scientific Amer., 62 (1985). These areas include faulty genes, accumulations of amyloid protein, infectious agents, environmental toxins (e g., aluminum and certain unusual amino acids), inadequate blood flow and energy metabolism, and cholinergic deficits.
A number of possible therapeutic interventions are currently under study. These include the use of nerve growth factors (NGF), muscarinic and nicotinic agonists, acetylcholinesterase (AChE) inhibitors, GABA-inverse agonists, NMDA modulators, and others. It is, however, unlikely that any single drug will restore cognition, especially in view of the involvement of a number of different neurotransmitter systems in memory processing.
While it is known that defects in neurotransmitter systems other than cholinergic systems play a role in the memory loss associated with Alzheimer's disease, findings by K. L. Davis, presented at "New Strategies for the Treatment of Alzheimer's Disease," NIA Meeting (Jan. 8-10, 1990) indicated that administration of AChE inhibitors, such as physostigmine, result in modest cognitive improvement and may prove useful for treating Alzheimer's disease when administered in combination with other drugs such as clonidine, deprenyl or desipramine.
To the extent ACHE inhibitors can serve as useful adjuncts in the treatment of Alzheimer's disease, two relatively new lycopodium alkaloids, (-)-huperzine A and B, isolated from Huperzia serrata (Thunb.) Trev., a Chinese folk medicine, appear superior to THA and physostigmine (U.S. Pat. No. 5,177,082 to Yu et al.; J. S. Liu et al., Can. J. Chem., 64, 837 (1986); W. A. Ayer et al., ibid., 67, 1077 (1989), ibid., 67, 1538 (1989)). The structure of (-)-huperzine A (1) is depicted below: ##STR2##
In studies performed in China, these compounds have been found to improve memory and learning in animals (X. C. Tang et al., Acta Pharmacol Sin., 7, 507 (1986)). Additionally, workers at Hoffman LaRoche studied (-)-huperzine A in mice and squirrel monkeys and found it to be an effective cognition enhancer (G. P. Vincent et al., Neurosci. Abst., 13, 884 (1987)). The duration of action of a single dose (2 mg/kg i.m.) of (-)-huperzine A is over 6 hr, a remarkable result in relation to the AChE inhibitory action of physostigmine (0.65 mg/kg i.m.), which has a maximal duration of action of 60 min and which causes considerable side effects (X. C. Tang et al., J. Neurosci. Res., 24, 276 (1989)). (-)-Huperzine A has been further tested in 128 patients suffering from myasthenia gravis and found to control the clinical manifestations of the disease in 99% of these cases (Y. S. Cheng, New Drugs and Clinical Remedies, 5, 197 (1986)).
Other pharmacological agents that circulate systemically but that are targeted to brain tissue have enjoyed only limited success. For such pharmacological agents to enter brain tissue in therapeutically effective concentrations, the blood-brain barrier, a network of tightly joined endothelial cells of central nervous system capillaries, must first be penetrated. Because the membranes of the endothelial cells are phospholipoidal in nature, pharmacological agents that are lipophilic in nature are better able to diffuse through the blood-brain barrier than those that are not (see Marcus E. Brewster et al., Chemical Approaches to Brain-Targeting of Biologically Active Compounds, in Drug Design for Neuroscience 435-67 (Alan P. Kozikowski ed., Raven Press, Ltd. 1993).
While huperzine A is a promising candidate for treatment of Alzheimer's disease, extraction of practical quantities from its natural source is difficult. Furthermore, only a limited number of huperzine A synthetic procedures have been disclosed, which are, for the most part, complicated and non-convergent, e.g., Kaneko et al., Tetrahedron, Asymmetry 8, 829-832 (1997); Chassaing el al., Synth. Conmnun. 27, 61-68 (1997); Kaneko et al., Tetrahedron 54, 5485-5506 (1998); Qian et al., Tetrahdron Leti. 30, 2089-2090 (1989)).
Accordingly, there remains a need for convergent synthetic methods toward huperzine A and precursors therefor.